New heterocyclic or benzenic derivatives of lipoic acid, their preparation and their use as medicaments

ABSTRACT

A subject of the invention is new heterocyclic or benzenic derivatives comprising a lateral chain derived from lipoic acid, which have an inhibitory activity on NO-synthase enzymes producing nitrogen monoxide NO and/or are agents allowing the regeneration of antioxidants or entities trapping the reactive oxygen species (ROS) and which intervene in a more general manner in the redox status of thiol groups. A subject of the invention is also their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as inhibitors of NO-synthases and/or as agents which intervene in a more general manner in the redox status of thiol groups.

A subject of the present invention is new heterocyclic or benzenicderivatives comprising a lateral chain derived from lipoic acid, whichhave an inhibitory activity on NO-synthase enzymes producing nitrogenmonoxide NO and/or are agents which allow the regeneration ofantioxidants or entities which trap the reactive oxygen species (ROS)and which intervene in a more general fashion in the redox status ofthiol groups. These antioxidants or entities which trap the reactiveoxygen species can be of natural origin, such as for example vitamin Eor glutathione, or of synthetic origin such as certain products whichtrap the ROS or products having both an inhibitory activity onNO-synthase enzymes and an activity which traps the ROS. Examples ofsuch products of synthetic origin can in particular be found in the PCTPatent Applications WO 96/09653, WO 98/42696 and WO 98/58934.

Therefore, the invention relates in particular to the derivativescorresponding to general formula (I) defined below, their preparationprocesses, the pharmaceutical preparations containing them and their usefor therapeutic purposes, in particular their use as NO-synthaseinhibitors and/or as agents which allow the regeneration of antioxidantsor entities which trap the ROS's and which intervene in a more generalfashion in the redox status of thiol groups.

Given the potential role of NO and the ROS's and the metabolism ofglutathione in physiopathology, the new derivatives describedcorresponding to general formula (I) may produce beneficial orfavourable effects in the treatment of pathologies where nitrogenmonoxide and the metabolism of glutathione as well as the redox statusof thiol groups are involved. In particular:

-   -   cardiovascular and cerebrovascular disorders including for        example atherosclerosis, migraine, arterial hypertension, septic        shock, ischemic or hemorragic Cardiac or cerebral infarctions,        ischemias and thromboses.    -   disorders of the central or peripheral nervous system such as        for example neurodegenerative diseases where there can in        particular be mentioned cerebral infarctions, sub-arachnoid        haemorrhaging, ageing, senile dementias including Alzheimer's        disease, Huntington's chorea, Parkinson's disease, Creutzfeld        Jacob disease and prion diseases, amyotrophic lateral sclerosis        but also pain, cerebral and spinal cord traumas, addiction to        opiates, alcohol and addictive substances, erective and        reproductive disorders, cognitive disorders, encephalopathies,        encephalopathies of viral or toxic origin, depression, anxiety,        schizophrenia, epilepsy, sleeping disorders, eating disorders        (anorexia, bulimia etc.);    -   disorders of the skeletal muscle and neuromuscular joints        (myopathy, myositis) as well as cutaneous diseases.    -   proliferative and inflammatory diseases such as for example        atherosclerosis, pulmonary hypertension, respiratory distress,        glomerulonephritis, cataracts, portal hypertension, psoriasis,        arthrosis and rheumatoid arthritis, fibroses, amyloidoses,        inflammations of the gastro-intestinal system (colitis, Crohn's        disease) or of the pulmonary system and airways (asthma,        sinusitis, rhinitis) as well as contact or delayed        hypersensitivities;    -   organ transplants.    -   auto-immune and viral diseases such as for example lupus, AIDS,        parasitic and viral infections, diabetes and its complications        including retinopathies, nephropathies and polyneuropathies,        multiple sclerosis, myopathies;    -   cancer.    -   autosomal genetic diseases such as Unverricht-Lundborg disease;    -   neurological diseases associated with intoxications (Cadmium        poisoning, inhalation of n-hexane, pesticides, herbicides),        associated with treatments (radiotherapy) or disorders of        genetic origin (Wilson's disease).    -   impotence linked to diabetes;    -   all the pathologies characterized by an excessive production or        a dysfunction of nitrogen monoxide and/or the metabolism of        glutathione and of the redox status of the thiol groups.

In all these pathologies, there is experimental evidence demonstratingthe involvement of nitrogen monoxide or of a dysfunction of themetabolism of glutathione (Kerwin et al., Nitric oxide: a new paradigmfor second messengers, J. Med. Chem. 38, 4343-4362, 1995; Packer et al.,Alpha-lipoic acid as biological antioxidant, Free Radical Biology &Medicine 19, 227-250, 1995). This is the case in particular inParkinson's disease (Beal M F, Excitotoxicity and nitric oxide inParkinson's disease pathogenesis. Ann. Neurol. 44[Suppl 1], S110-S114,1998; Donato et al., Gluthathion in Parkinson's disease: a link betweenoxidative stress and mitochondrial damage. Ann. Neurol. 32, S111-S115,1992). In this context, medicaments which can inhibit the formation ofnitrogen monoxide or re-establish the biological functionality of thethiol groups or glutathione can have beneficial effects.

Moreover, in earlier patents, the inventors have already described NOSynthase inhibitors and their use (U.S. Pat. Nos. 5,081,148; 5,360,925)and more recently the combination of these inhibitors with productshaving antioxidant or antiradicular properties (PCT Patent ApplicationWO 98/09653). They have also described derivatives of amidines in PCTPatent Applications WO 98/42696 and WO 98/58934 and the derivatives ofaminopyridines in the PCT Patent Application WO 00/02860. Thesederivatives of amidines or aminopyridines have the characteristic ofbeing both is NO Synthase inhibitors and ROS inhibitors

A subject of the present invention is new heterocyclic or benzenicderivatives comprising a lateral chain derived from lipoic acid, theirpreparation and their therapeutic use.

The invention relates therefore to a product of general formula (I),characterized in that it comprises the products of sub-formulae (I)a and(I)b

in which

-   n represents an integer from 0 to 6;-   R₁ and R₂ represent, independently, a hydrogen atom or a linear or    branched alkyl radical with 1 to 6 carbon atoms;-   X—Y represents —O—(CH₂)_(r)—, —N(R₃)—(CH₂)_(r)—, —CO(CH₂)_(r)—,    —CO—N(R₃)—(CH₂)_(r)—, —N(R₄)—CO—(CH₂)_(r)—, or    —N(R₃)—CO—N(R₄)—(CH₂)_(r)—,-   X′—Y′ represents —(CH₂)_(r)—, —(CH₂)_(r)—O—(CH₂)_(r)—,    —(CH₂)_(r)—N(R₃)—(CH₂)_(r)—, —(CH₂)_(r)—CO(CH₂)_(r)—,    —(CH₂)_(r)—CO—N(R₃)—(CH₂)_(r)—, —(CH₂)_(r)—N(R₄)—CO—(CH₂)_(r)— or    —(CH₂)_(r)—N(R₃)—CO—N(R₄)—(CH₂)_(r)—,-   R₃ and R₄ represent, independently each time that they occur, a    hydrogen atom or an alkyl, alkoxycarbonyl or aralkoxycarbonyl    radical;-   r representing independently each time that it occurs an integer    from 0 to 6;-   Ω represents an aromatic heterocycle with 5 or 6 members, a non    aromatic heterocycle with 4 to 7 members or a phenylene radical    substituted by an R₅ radical, R₅ representing a hydrogen atom, a    linear or branched alkyl radical with 1 to 6 carbon atoms or a    —(CH₂)_(m)-Q radical in which Q represents a halogen atom or a    hydroxy, cyano, amino, alkoxy, alkylamino or dialkylamino radical, m    representing an integer from 0 to 6;-   P represents —(CH₂)_(g)—, g representing an integer from 0 to 6, or    also P represents an    radical in which R₆ represents a hydrogen atom, a linear or branched    alkyl radical with 1 to 6 carbon atoms or a —(CH₂)_(n)-Q′ radical in    which Q′ represents a halogen atom or a trifluoromethyl, hydroxy,    amino, cyano, alkoxycarbonylamino, aralkoxycarbonylamino, alkoxy,    alkylthio, alkylamino or dialkylamino radical and n represents an    integer from 0 to 6, or also R₆ represents an aromatic or non    aromatic heterocycle with 5 to 6 members the heterocyclic members of    which are chosen from the —O—, —N(R₇)— and —S— radicals, R₇    representing a hydrogen atom or a linear or branched alkyl with 1 to    6 carbon atoms;-   and finally A represents the    radical in which:-   B represents a linear or branched alkyl radical with 1 to 6 carbon    atoms, carbocyclic or heterocyclic aryl radical with 5 or 6 members    containing from 1 to 4 heteroatoms chosen from O, S and N and in    particular the thiophene, furan, pyrrole or thiazole radicals, the    aryl radical being optionally substituted by one or more groups    chosen from the linear or branched alkyl, alkenyl or alkoxy radicals    with 1 to 6 carbon atoms, or B represents NR₈R₉, in which R₈ and R₉    represent, independently, a hydrogen atom or a linear or branched    alkyl radical with 1 to 6 carbon atoms, or one of R₈ and R₉    represents a nitro radical whilst the other represents a hydrogen    atom or a linear or branched alkyl radical with 1 to 6 carbon atoms,    or also R₈ and R₉ when taken together form with the nitrogen atom a    non aromatic heterocycle with five to six members, the elements of    the chain being chosen from a group comprising —CH₂—, —NH—, —O— or    —S—, or also B represents an SR₁₀ radical in which R₁₀ represents a    hydrogen atom or a linear or branched alkyl radical with 1 to 6    carbon atoms;    or a salt of a product of general formula (I).

By alkyl, unless otherwise specified, is meant a linear or branchedalkyl radical containing 1 to 6 carbon atoms. By cycloalkyl, unlessotherwise specified, is meant a monocyclic carbon system containing 3 to7 carbon atoms. By alkenyl, unless otherwise specified, is meant alinear or branched alkyl radical containing 1 to 6 carbon atoms and withat least one unsaturation (double bond). By alkynyl, unless otherwisespecified, is meant a linear or branched alkyl radical containing 1 to 6carbon atoms and with at least one double unsaturation (triple bond). Byalkenyl, is meant the —CH═C═CH₂ radical. By carbocyclic or heterocyclicaryl, is meant a carbocyclic (in particular, the phenyl radical whichcan be abbreviated to Ph) or heterocyclic system comprising at least onearomatic ring, a system being called heterocyclic when at least one ofthe rings which comprises it contains a heteroatom (O, N or S). Byheterocycle, unless otherwise specified, is meant a mono- or polycyclicsystem said system comprising at least one heteroatom chosen from O, Nand S and being saturated, partially or totally unsaturated or aromatic.By heteroaryl, unless otherwise specified, is meant a heterocycle asdefined previously in which at least one of the rings which comprise itis aromatic. By haloalkyl, is meant an alkyl radical at least one of thehydrogen atoms (and optionally all) of which is replaced by a halogenatom.

By alkylthio, alkoxy, haloalkyl, alkoxyalkyl, trifluoromethylalkyl,cycloalkylalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, allenylalkyl,cyanoalkyl and aralkyl radicals, is meant respectively the alkylthio,alkoxy, haloalkyl, alkoxyalkyl, trifluoromethylalkyl, cycloalkylalkyl,haloalkoxy, aminoalkyl, alkenyl, alkynyl, allenylalkyl, cyanoalkyl andaralkyl radicals the alkyl radical (the alkyl radicals) of which havethe meaning(s) indicated previously.

By heterocycle, is meant in particular the thienyl, piperidyl,piperazinyl, quinolinyl, indolinyl and indolyl radicals. By linear orbranched alkyl with 1 to 6 carbon atoms, is meant in particular themethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl andtert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals.Finally, by halogen, is meant the fluorine, chlorine, bromine or iodineatoms.

Preferably, the invention relates to the compounds of general formula(I) in which at least one of the following characteristics is found:

-   -   n represents an integer from 1 to 6;    -   X—Y represents one of the O—(CH₂)_(r)—, —N(R₃)—(CH₂)_(r)—,        —CO(CH₂)_(r)—, —CO—N(R₃)—(CH₂)_(r)—, —N(R₄)—CO—(CH₂)_(r)—, or        —N(R₃)—CO—N(R₄)—(CH₂)_(r)— radicals, in which R₃ and R₄        represent a hydrogen atom or an alkyl radical;    -   X′—Y′ represents one of the —(CH₂)_(r)—,        —(CH₂)_(r)—O—(CH₂)_(r)—, —(CH₂)_(r)—N(R₃)—(CH₂)_(r)—,        —(CH₂)_(r)—CO(CH₂)_(r)—, —(CH₂)_(r)—CO—N(R₃)—(CH₂)_(r)—,        —(CH₂)_(r)—N(R₄)—CO—(CH₂)_(r)— or        —(CH₂)_(r)—N(R₃)—CO—N(R₄)—(CH₂)_(r)— radicals, in which R₃ and        R₄ represent a hydrogen atom or an alkyl or alkoxycarbonyl        radical;        Ω represents a phenylene radical substituted by an R₅ radical,        R₅ representing a hydrogen atom, a linear or branched alkyl        radical with 1 to 6 carbon atoms or a —(CH₂)_(m)-Q radical in        which Q represents a halogen atom or a cyano, amino or alkoxy,        radical, m representing an integer from 0 to 6, or also Ω        represents an aromatic heterocycle with 5 or 6 members or a non        aromatic heterocycle with 4 to 7 members, said aromatic or non        aromatic heterocycle preferably comprising at least one nitrogen        atom;    -   P represents a    -   A represents a    -   radical in which B represents a carbocyclic or heterocyclic aryl        radical with 5 or 6 members containing from 1 to 4 heteroatoms        chosen from O, S and N.

More preferentially, the invention relates to the compounds of generalformula (I) in which at least one of the following characteristics isfound:

-   -   n represents an integer from 1 to 5;    -   X—Y represents one of the —O—(CH₂)_(r)—, —N(R₃)—(CH₂)_(r)—,        —CO(CH₂)_(r)—, —CO—N(R₃)—(CH₂)_(r)—, —N(R₄)—CO—(CH₂)_(r)—, or        —N(R₃)—CO—N(R₄)—(CH₂)_(r)— radicals, in which R₃ and R₄        represent a hydrogen atom;    -   X′—Y′ represents one of the —(CH₂)_(r)—,        —(CH₂)_(r)—O—(CH₂)_(r)—, —(CH₂)_(r)—N(R₃)—(CH₂)_(r)—,        —(CH₂)_(r)—CO(CH₂)_(r)—, —(CH₂)_(r)—CO—N(R₃)—(CH₂)_(r)—,        —(CH₂)_(r)—N(R₄)—CO—(CH₂)_(r)— or        —(CH₂)_(r)—N(R₃)—CO—N(R₄)—(CH₂)_(r)— radicals, in which R₃ and        R₄ represent a hydrogen atom;    -   Ω represents a phenylene radical substituted by an R₅ radical,        R₅ representing a hydrogen atom, a linear or branched alkyl        radical with 1 to 6 carbon atoms or a —(CH₂)_(m)-Q radical in        which Q represents a cyano, or alkoxy radical, or also Ω        represents a non aromatic heterocycle with 4 to 7 members        preferably comprising at least one nitrogen atom;    -   P represents a    -   radical in which R₆ represents a —(CH₂)_(n)-Q′ radical in which        Q′ represents a hydrogen atom or an alkoxy, cyano, amino,        alkylamino or dialkylamino radical and n represents an integer        from 0 to 6 and preferably an integer from 0 to 3;    -   A represents a    -   radical in which B represents a heterocyclic aryl radical with 5        or 6 members containing from 1 to 4 heteroatoms chosen from O, S        and N.

Even more preferentially, the invention relates to the compounds ofgeneral formula (I) in which at least one of the followingcharacteristics is found:

-   -   n represents an integer from 1 to 4;    -   X—Y represents one of the —CO(CH₂)_(r)—, —CO—N(R₃)—(CH₂)_(r)— or        —N(R₄)—CO—(CH₂)_(r)— radicals, in which R₃ and R₄ represent a        hydrogen atom;    -   X′—Y′ represents one of the —(CH₂)_(r)— or        —(CH₂)_(r)—N(R₃)—(CH₂)_(r)— or —(CH₂)_(r)—CO—N(R₃)—(CH₂)_(r)—        radicals, in which R₃ and R₄ represent a hydrogen atom;    -   Ω represents a piperazinyl, piperidyl or phenyl radical, and        preferably a piperazinyl or piperidyl radical;    -   P represents a    -   radical in which R₆ represents a —(CH₂)_(n)-Q′ radical in which        Q′ represents a hydrogen atom or an alkoxy, cyano or amino        radical and n represents an integer from 0 to 3;    -   A represents an    -   radical in which B represents a thienyl, furanyl or pyrrolyl        radical.

Moreover, among the compounds of general formula (I) the compoundscorresponding to sub-general formula (I)a are generally preferred.

More particularly, the invention relates to the following productsdescribed in the examples (sometimes in the form of salts):

-   N′-(4-{4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;-   N′-(4-{4-[2-(1,2-dithiolan-3-yl)acetyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;-   N′-[3-({4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl}methyl)phenyl]-2-thiophenecarboximidamide;-   N′-[3-({4-[2-(1,2-dithiolan-3-yl)acetyl]-1-piperazinyl}methyl)phenyl]-2-thiophenecarboximidamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}-2-methylphenyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}-3-methylphenyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}-2-methoxyphenyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}-3-methoxyphenyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}-2-cyanophenyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide;-   4-(3-{[amino(2-thienyl)methylidene]amino}benzyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide;-   N′-(3-{4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;-   tert-butyl    5-{[amino(2-thienyl)methylidene]amino}-2-{4-[5-(1,2-dithiolan-3-yl)    pentanoyl]-1-piperazinyl}benzylcarbamate;-   N′-(3-(aminomethyl)-4-{4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;-   tert-butyl 3-{[-amino(2-thienyl)methylidene]amino}benzyl    {1-[5-(1,2-dithiolan-3-yl) pentanoyl]-4-piperidinyl}carbamate;-   N′-{3-[({1-[5-(1,2-dithiolan-3-yl)pentanoyl]-4-piperidinyl}amino)methyl]phenyl}-2-thiophenecarboximidamide;-   N-[2-(4-{[amino(2-thienyl)methylidene]amino}phenyl)ethyl]-4-{[5-(1,2-dithiolan-3-yl)pentanoyl]amino}benzamide;    and their salts, in particular the corresponding hydrochlorides.

In addition the invention offers a certain number of processes to accessthe products of general formula (I) described above, the preferredconditions of which processes are described below.

Therefore the invention in particular relates to a process for thepreparation of a compound of general formula (I) as defined previously,characterized in that a compound of general formula (II)

in which n, X, Y, Ω, X′, Y′ and P have the same meaning as in generalformula (I) is reacted,

-   a) with the compound of general formula (I.i)    in which B has the same meaning as in general formula (I) and L    represents a parting group, for example an alkoxy, alkylthio,    sulphonic acid, halide, aryl alcohol or tosyl radical,-   b) or with the compound of general formula (I.ii)    in which L represents a parting group, for example an alkoxy,    alkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical,-   c) or with the compound of general formula (I.iii)    in which L represents a parting group, for example an alkoxy,    alkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical,    and Gp a protective group of carbamate type, for example the    t-butoxycarbonyl group,    this reaction being followed, in the case where the reaction with    the compound of general formula (I.iii) is chosen, by hydrolysis in    the presence of a strong acid, for example trifluoroacetic acid,-   d) or with the derivative of formula (I.iv)    (N-methyl-N′-nitro-N-nitrosoguanidine)-   e) or finally with the derivative of formula (I.v) in which Gp    represents a protective group

The invention also relates to a process for the preparation of a productof general formula (I) in which the X—Y group represents—CO—N(R₃)—(CH₂)_(r)—, characterized in that the acid of general formula(I.vi)

in which n has the same meaning as in general formula (I), is reactedwith an amine of general formula (X) or (Xa)

in which r, R₃, Ω, X′, Y′, P and A have the same meaning as in generalformula (I), the compound of general formula (Xa) being moreover suchthat its Ω heterocycle comprises a nitrogen atom.

A subject of the invention is also, as new products, synthesisintermediates useful for the preparation of compounds of general formula(I), namely the compounds of general formulae (II), (III), (IV), (X),(Xa), (XI) and (XIa) as defined above for (II), (X) and (Xa), andfurther on for (III), (IV), (XI) and (XIa).

In certain cases, the compounds according to the present invention cancomprise asymmetrical carbon atoms, and therefore possess two possibleenantiomeric forms, i.e. the “R” and “S” configurations. The presentinvention includes the two enantiomeric forms and all combinations ofthese forms, including the racemic “RS” mixtures. The present inventionincludes the two enantiomeric forms and all combinations of these forms,including the racemic “RS” mixtures. For the sake of simplicity, when nospecific configuration is indicated in the structural formulae, itshould be understood that the two enantiomeric forms and their mixturesare represented.

A subject of the invention is also, as medicaments, the compoundsdescribed previously or their pharmaceutically acceptable salts. It alsorelates to pharmaceutical compositions containing these compounds ortheir pharmaceutically acceptable salts, and the use of these compoundsor of their pharmaceutically acceptable salts for producing medicamentsintended to inhibit neuronal NO synthase or inducible NO synthase, toregenerate anti-oxidants, which can be natural or synthetic or to ensurethe double function of inhibition of NO synthase and regeneration ofanti-oxidants.

By pharmaceutically acceptable salt is meant in particular additionsalts of inorganic acids such as hydrochloride, hydrobromide,hydroiodide, sulphate, phosphate, diphosphate and nitrate, or of organicacids, such as acetate, maleate, fumarate, tartrate, succinate, citrate,lactate, methane sulphonate, p-toluenesulphonate, pamoate and stearate.The salts formed from bases such as sodium or potassium hydroxide alsofall within the scope of the present invention, when they can be used.For other examples of pharmaceutically acceptable salts, reference canbe made to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33,201-217.

A subject of the invention is also the use of a product of generalformula (I) or a pharmaceutically acceptable salt of this product forpreparing a medicament intended to treat pathologies in which nitrogenmonoxide and/or the redox status of the thiol groups are involved,pathologies such as disorders of the central or peripheral nervoussystem particularly well represented by Parkinson's disease,cerebro-vascular disorders, proliferative and inflammatory diseases,vomiting, septic shock, pathologies resulting from radioactiveirradiation, solar radiation or organ transplantation, auto-immune andautosomal diseases, cancer and all the pathologies characterised byproduction or dysfunction involving nitrogen monoxide and/or involvingthe redox status of the thiol groups.

A subject of the invention is also the use of a product of generalformula (I) or of a pharmaceutically acceptable salt of this product, inorder to produce a medicament intended to treat cerebro-vasculardisorders such as migraine, ischemic or hemorrhagic cerebral infarction,ischemias and thromboses.

Finally a subject of the invention is also the use of a product ofgeneral formula (I) or of a pharmaceutically acceptable salt of thisproduct, in order to produce a medicament intended to treat disorders ofthe central or peripheral nervous system such as for exampleneurodegenerative diseases, pain and fibromyalgia, cerebral and spinalcord traumas, diabetes and its complications including retinopathies,nephropathies and polyneuropathies, addiction to opiates, alcohol andaddictive substances, erective and reproductive disorders, cognitivedisorders, encephalopathies, depression, anxiety, schizophrenia,epilepsy, sleeping disorders and alimentary disorders.

The pharmaceutical compositions can be in the form of a solid, forexample powders, granules, tablets, capsules, liposomes orsuppositories. Appropriate solid supports can be for example calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the inventioncan also be presented in the form of a liquid, for example, solutions,emulsions, suspensions or syrups. Appropriate liquid supports can be,for example, water, organic solvents such as glycerol or glycols, aswell as their mixtures, in varying proportions, in water.

A medicament according to the invention can be administered by topical,oral or parenteral route, by intramuscular injection, etc.

The envisaged administration dose for the medicament according to theinvention is comprised between 0.1 mg and 10 g according to the type ofactive compound used.

According to the invention, the compounds of general formula (I) can beprepared by the process described below.

Preparation of the Compounds of the Invention

A) First Approach

The compounds of general formula (I) can be prepared from theintermediates of general formula (II), (III) and (IV) according toDiagram 1 where n, X, X′, Y, Y′, Ω, P and A are as defined above and Gpis a protective group of carbamate type.

The aniline and amine derivatives of general formula (II), can becondensed with the compounds of general formula (I.i), in which Lrepresents a parting group (in particular an alkoxy, thioalkyl,sulphonic acid, halide, aryl alcohol or tosyl radical), in order toproduce the final compounds of general formula (I) of substitutedamidine type (cf. Diagram 1). For example, for B=thiophene, thederivatives of general formula (II) can be condensed withS-methylthiophene thiocarboxamide hydroiodide, prepared according to aprocess in literature (Ann. Chim. (1962), 7, 303-337). Condensation canbe carried out by heating in an alcohol (for example in methanol orisopropanol), optionally in the presence of DMF at a temperaturepreferably comprised between 50 and 100° C. for a duration generallycomprised between a few hours and overnight.

In the case where B=SR₁₀, for example S—CH₃, it can be prepared bycondensation of the amines or anilines of general formula (II) with theisothiocyanate (I.v) in which Gp represents a protective group such asfor example the benzoyl group. Deprotection is then carried out bycleavage of the protective group under appropriate conditions and thethiourea formed is finally treated with, for example, a halogeno alkanein order to produce the final compounds of general formula (I).

In the case where B=NR₈R₉, the final compounds of general formula (I)are guanidines. These can be prepared, for example, by condensation ofthe amines or anilines of general formula (II) with the derivatives ofgeneral formula (I.ii) or (I.iii). The reagents of general formula(I.ii) in which L represents, for example, a pyrazole ring are condensedwith the amines of general formula (II) according to the conditionsdescribed in literature (J. Org. Chem. (1992) 57, 2497-2502). Similarlyfor the reagents of general formula (I.iii) in which L represents, forexample, a pyrazole ring and Gp the tBuOCO group (Tetrahedron Lett.(1993) 34 (21), 3389-3392) or when L represents the —N—SO₂—CF₃ group andGp the tBuOCO group (J. Org. Chem. (1998) 63, 3804-3805). During thefinal stage of synthesis, the deprotection of the guanidine function iscarried out in the presence of a strong acid such as for exampletrifluoroacetic acid.

In the case where B=—NHNO₂ the final compounds of general formula (I)can be prepared, for example, by condensation of the amines or anilinesof general formula (II) with the reagent of formula (I.iv)(N-methyl-N′-nitro-N-nitrosoguanidine) according to the conditionsdescribed in literature (J. Amer. Chem. Soc. (1947), 69, 3028-3030).

The compounds of general formula (I)b, are obtained from the compoundsof general formula (I)a where n, X, X′, Y, Y′, Ω, P and A are as definedabove. Conversion of the lipoic compounds of general formula (I)a to thecorresponding dihydrolipoic derivatives (I)b where R₁=R₂=H is carriedout in alcoholic solvent such as, for example, methanol, in the presenceof a reducing agent such as for example NaBH₄, NaBH₃CN or lithiumaluminium hydride (LAH). The compounds for which R₁ and R₂ do not bothrepresent H are prepared by reacting the compounds of general formula(I)b with a compound of formula R₁-halogen and/or R₂-halogen where R₁and R₂ are as defined above and the atom halogen is a parting group. Thereaction is carried out, for example, in an appropriate solvent such asTHF, acetone, ethyl acetate in the presence of a base such as K₂CO₃ ortriethylamine, in order to produce the compounds of general formula(I)b.

Preparation of the Compounds of General Formula (II):

The intermediates of general formula (II), are obtained from thecleavage of a protective group (Gp) or by reduction of a nitro group.

The intermediates of general formula (II), in which n, X, X′, Y, Y′, Ω,and P are as defined above, can be prepared from the intermediates ofgeneral formula (III) or (IV), Diagram 1, which are compounds comprisingrespectively a protected amine or aniline (NHGp) in the form, forexample, of a carbamate or a nitro group. In the particular case of BOCgroups, these are deprotected in a standard fashion using TFA or HCl, inorder, finally to produce the primary amines and anilines of generalformula (II). Reduction of the nitro function of the intermediates ofgeneral formula (IV), Diagram 1, in which n, X, X′, Y, Y′, Ω, and P areas defined above, is carried out, for example, by heating the product inan appropriate solvent such as ethyl acetate with a little ethanol inthe presence of SnCl₂ (J. Heterocyclic Chem. (1987), 24, 927-930;Tetrahedron Letters (1984), 25 (8), 839-842) in the presence of SnCl₂/Zn(Synthesis. (1996), 9.1076-1078), using NaBH₄—BiCl₃ (Synth. Com. (1995)25 (23), 3799-3803) in a solvent such as ethanol, or then by usingRaney-Ni with added hydrazine hydrate (Monatshefte für Chemie, (1995),126, 725-732), or using indium in a mixture of ethanol and ammoniumchloride under reflux (Synlett (1998) 9, 1028). Then the product ofdouble reduction is re-oxidized in the presence of ferric chloride(FeCl₃) (Synlett (1991) 10, 717-718) or iodine (Tetrahedron Letters.(1997), 38 (33), 5785-5788) in order to finally produce the amines andanilines of general formula (II) again containing the dithiolane unit.

Preparation of the Compounds of General Formula (II) and (IV):

Synthesis of the Carboxamides of General Formula (III) and (IV):

The carboxamides of general formula (III) and (IV) in which n, X, Y, X′,Y′, Ωand P are as defined above, which can have either an amide functionthe nitrogen of which belongs to the Ω heterocycle, or an amide functionthe nitrogen of which is fixed to the Ω radical or to an alkylene chainlinked to this radical, Diagram 2 are prepared by condensation of theacids of general formula (I.vi) with the monoprotected amines oranilines of general formula (VI) and (VIII) or the nitro derivatives ofgeneral formula (VII) and (IX). The carboxamide bonds are formed understandard conditions of peptide synthesis (M. Bodanszky and A. Bodanszky,The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF,dichloromethane or DMF in the presence of a coupling reagent such asdicyclohexylcarbodiimide (DCC), 1.1′-carbonyldiimidazole (CDI) (J. Med.Chem. (1992), 35 (23), 4464-4472) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC orWSCI) (John Jones, The chemical synthesis of peptides, 54 (ClarendonPress, Oxford, 1991)) or in the presence of isobutyl chloroformate andN-methyl morpholine (Org. Prep. Proced. Int., (1975), 35, 215). Thesyntheses of the carboxylic acids of general formula (I.vi) and theamines/anilines of general formula (VI), (VII), (VIII) and (IX) whichare not commercially available, are described below.

B) Second Approach

The compounds of general formula (I) can also be prepared from theintermediates of general formula (X), (XI), (XII) and (XIII) (or (Xa),(XIa), (XIIa) and (XIIIa) when the amine function forms part of the Ωheterocycle) according to Diagram 3 in which n, X, X′, Y, Y′, Ω, P and Aare as defined above and Gp₁ and Gp₂ are protective groups: for example,when Y=—NR₃—, Gp₁ can be a protective group of carbamate type or whenY=—O—, Gp₁ can be a protective group of benzyl type or other protectivegroups (Gp₁) known to a person skilled in the art. Gp₂ can also be aprotective group of carbamate type or other protective groups (Gp₂)known to a person skilled in the art.

Preparation of the Compounds of General Formula (I):Synthesis of the Carboxamides of General Formula (I):

The carboxamides of general formula (I), Diagram 4, in which n, X′, Y′,Ω, P and A are as defined above, are prepared by condensation of theacids of general formula (I.vi) with the amines/anilines of generalformula (X) and (X)a. The carboxamide bonds are formed under standardconditions of peptide synthesis (M. Bodanszky and A. Bodanszky, ThePractice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF,dichloromethane or DMF, in the presence of a coupling reagent such asdicyclohexylcarbodiimide (DCC), 1.1′-carbonyldiimidazole (CDI) (J. Med.Chem. (1992), 35 (23), 4464-4472) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC orWSCI) (John Jones, The chemical synthesis of peptides, 54 (ClarendonPress, Oxford, 1991)) or in the presence of isobutyl chloroformate andN-methyl morpholine (Org. Prep. Proced. Int., (1975), 35, 215). Thesyntheses of the carboxylic acids of general formula (I.vi) which arenot commercially available, are described below.

Synthesis of the Ureas of General Formula (I)

The ureas of general formula (I), Diagram 5, in which n, X′, Y′, Ω, Pand A are as defined above, are prepared, for example, by condensationof the acids of general formula (I.vi) with the amines/anilines ofgeneral formula (X) and (X)a in toluene in the presence ofdiphenylphosphoryl azide (DPPA) and triethylamine, for example at atemperature of 80° C. and for 2 to 3 hours.

Preparation of the Compounds of General Formula (X), (X)a, (XI), (XI)a,(XII), (XII)a, (XIII) and (XIII)a:

The compounds of general formula (X) and (X)a are obtained from thecleavage of a protective group. The compounds of general formula (X) and(X)a, in which X′, Y, Y′, Ω, P and A are as defined above, can beprepared from the compounds of general formula (XI) and (XI)a, Diagram3, which are compounds comprising a protected amine/aniline (NHGp) inthe form, for example, of a carbamate or an alcohol or phenol protectedby a benzyl group (O-benzyl) or by other protective groups (Gp₁, Gp₂)known to a person skilled in the art. In the particular case of the BOCgroups, these are deprotected in a standard fashion usingtrifluoroacetic acid (TFA) or HCl, the O-benzyl groups being themselvesdeprotected in a standard fashion by catalytic hydrogenation in thepresence of Pd on carbon, and the compounds of general formula (X) and(X)a are finally obtained.

The compounds of general formula (XI) and (XI)a can be prepared from theintermediates of general formula (XII) and (XII)a and (XIII) and (XIII)aaccording to Diagram 3 where Ω, Y, X′, Y′, P are as defined above andGp₁ and Gp₂ are protective groups.

The aniline/amine derivatives of general formula (XII) and (XII)a can becondensed with compounds of general formula (I.i, Iii, and Iiii), inwhich L represents a parting group and with (I.iv and I.v) as previouslydescribed for the compounds of general formula (I) in Diagram 1, inorder to finally produce to the compounds of general formula (X) and(X)a, Diagram 3.

The compounds of general formula (XII) and (XII)a, are obtained from thereduction of a nitro group of the compounds of general formula (XIII)and (XIII)a. Reduction of the nitro function of the compounds of generalformula (XIII) and (XIII)a, Diagram 3, in which Ω, Y, X′, Y′ and P areas defined above, is carried out, for example, in a standard fashion bycatalytic hydrogenation in the presence of Pd on carbon, or by heatingthe product in an appropriate solvent such as ethyl acetate with alittle ethanol in the presence of SnCl₂ (J. Heterocyclic Chem. (1987),24, 927-930; Tetrahedron Letters (1984), 25 (8), 839-842), in thepresence of SnCl₂/Zn (Synthesis. (1996), 9.1076-1078) or also usingNaBH₄—BiCl₃ (Synth. Com. (1995) 25 (23), 3799-3803) in a solvent such asethanol, or then by using Raney-Ni with added hydrazine hydrate(Monatshefte für Chemie, (1995), 126, 725-732), or finally using indiumin a mixture of ethanol and ammonium chloride under reflux (Synlett(1998) 9, 1028), in order to finally produce the primary amines andanilines of general formula (XII) and (XII)a.

The synthesis of the compounds of general formula (XIII) and (XIII)awhich are not commercially available, is described below.

Preparation of Certain Synthesis Intermediates which are notCommercially Available:

The acids of general formula (I.vi) which are not commerciallyavailable, in which m is as defined above are accessible from processesin literature. For example, trisnorlipoic acid[2-(1,2-dithiolan-3-yl)-acetic acid] is obtained in 5 stages accordingto an experimental protocol described in Tetrahedron Letters. (1997), 38(33), 5785-5788.

The compounds of general formula (XIII)a in which P represents aphenylene radical, Ω represents a piperazinyl or homopiperazinyl radical(T represents the —(CH₂)_(x)— radical with x=2 or 3) and r and R are asdefined in general formula (I), Diagram 3.1, are prepared from thehalogenated derivatives of general formula (XIII.1)a. The latter aresubjected to a nucleophilic substitution by a heterocyclic compound ofgeneral formula (XIII.2)a in a solvent such as DMSO, DMF, acetone ordichloromethane in the presence of a base such as K₂CO₃, KOH, NaOH ortriethylamine, in order to produce the intermediates of general formula(XIII)a.

Certain compounds of general formula (XIII)a in which P represents aphenylene radical, Ω represents a piperidine, homopiperidine orpyrrolidine radical (T represents the —(CH₂)_(y)— radical with y=1, 2 or3) and R₆ is as defined in general formula (I) can be prepared, Diagram3.2, from the substituted nitrobenzaldehydes of general formula(XIII.3)a. The substituted compounds of general formula (XIII.3)a arecondensed with an amine of general formula (XIII.4)a in reducing medium.The reaction takes place in alcoholic solvent such as, for example,methanol, in the presence of a reducing agent such as, for example,NaBH₄ or NaBH₃CN. When R₃=H, the protection of the free amine functionof the compounds of general formula (XIII)a, is carried out in astandard fashion with (Boc)₂ in dichloromethane or by other protectiontechniques known to a person skilled in the art.

The compounds of general formula (XIII)a in which P represents aphenylene radical, Ω represents a piperazinyl or homopiperazinyl radical(T represents the —(CH₂)_(z)— radical with z=2 or 3), r is as definedabove and R₆ is an aminomethyl radical protected by a protective groupGp₂, Diagram 3.3, are prepared from the halogenated derivatives ofgeneral formula (XIII.5)a. The reduction of the nitrile function of theintermediates of general formula (XIII.6)a is carried out, for example,in an appropriate solvent such as ether or THF, in the presence of areducing agent such as for example diborane. The protection of theprimary amine formed is then carried out in a standard fashion with(Boc)₂ in dichloromethane or by other protection techniques known to aperson skilled in the art in order to produce the compounds of generalformula (XII)a.

The compounds of general formula (XI) in which Ω represents a phenyleneradical substituted by an R₅ radical and r is as defined in generalformula (I), are prepared, Diagram 3.4, by peptide coupling (understandard conditions of peptide synthesis such as those already describedpreviously) of the acids of general formula (XI.1) with the amines ofgeneral formula (XI.2). Preparation of the amines of general formula(XI.2) can be carried out, for example, in a similar manner with theoperating method of Stages 17.2 to 17.6 of Example 17 described below.The R₅ group is optionally protected beforehand when it comprises anamine, aniline, alcohol or free phenol function, the deprotection ofsaid amine, aniline, alcohol or free phenol function having in principletaken place once the peptide coupling reaction between the compound ofgeneral formula (I.vi) and the compound of general formula (X) iscarried out (these reactions, carried out according to current processesfor a person skilled in the art, are not indicated in Diagram 3.4).

Unless otherwise specified, all the technical and scientific terms usedhere have the same meaning as that commonly understood by an ordinaryspecialist in the field to which the invention belongs. Similarly, allpublications, patent applications, all patents and all other referencesmentioned here are incorporated by way of reference.

The following examples are presented to illustrate the above proceduresand must in no case be considered as a limit to the scope of theinvention.

EXAMPLES Example 1N′-(4-{4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl)phenyl)-2-thiophenecarboximidamidehydrochloride

A. Process According to the First Approach

1.A.1) 1-[5-(1,2-dithiolan-3-yl)pentanoyl]-4-(4-nitrophenyl)piperazine

5.0 g (24.13 mmol) of nitrophenylpiperazine, triethylamine (14.0 ml),4.24 g (31.37 mmol) hydroxybenzotriazole and 12.0 g (62.73 mmol)1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride are addedsuccessively to a solution of 5.0 g (24.13 mmol) (DL)-thioctic acid in120 ml of dichloromethane. After having stirred the reaction mixtureovernight at 25° C., the mixture is diluted with 400 ml of water and thestirring is maintained for an additional 30 minutes. The product isextracted using 3 times 200 ml of dichloromethane. The organic solutionis dried over magnesium sulphate, filtered and concentrated undervacuum. The solid obtained is filtered and rinsed with diethyl ether inorder to obtain, after drying, 6.21 g of a yellow solid product with ayield of 65%. Melting point: 97.6-98.5° C.

1.A.2) 4-(4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl}aniline

16 ml of a saturated aqueous solution of ammonium chloride and 21.0 g(0.183 mol) of powdered Indium is added successively to a solution of5.2 g (13.20 mmol) of intermediate 1.A.1 in 60 ml of ethanol then thereaction medium is taken to reflux for 5 hours (Synlett (1998) 9, 1028).The mixture is cooled down to ambient temperature and filtered oncelite. The filtrate is alkalinized to pH 10 with a 50% solution ofsodium hydroxide. The reduced product is extracted using 4 times 150 mlof dichloromethane. The organic solution is dried over magnesiumsulphate, followed by filtration and concentration under vacuum in orderto produce a yellow oil. The oil is dissolved in a mixture of 15 ml ofdimethylformamide and 20 ml of ethyl acetate. The medium is cooled downusing an ice bath, to 0° C., and a 10% aqueous solution of potassiumbicarbonate is added dropwise. After having stirred the reaction mixturefor approximately 10 minutes at 0° C., iodine solution (3.45 g in 40 mlof ethyl acetate) is added dropwise until the iodine colourationremains. The product is extracted using 4 times 100 ml of ethyl acetate,the organic solution is dried over magnesium sulphate, followed byfiltration and concentration under vacuum. Purification on a silicacolumn (eluent=5% ethanol in dichloromethane) is then carried out inorder to produce a yellow oil, 3.03 g, with a yield of 63%.

MH⁺=366.2.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.39 (m, 2H, CH₂); 1.50-1.70 (m, 4H, CH₂);1.87 (m, 1H, CH₂); 2.32 (m, 2H, CH₂); 2.34 (m, 1H, CH₂); 2.80-2.88 (m,4H, CH₂-piperazine); 3.17 (m, 2H, CH₂); 3.53 (m, 4H, CH₂-piperazine);3.59 (m, 1H, —S—CH—); 4.58 (s, 2H, NH₂); 6.50 (d, 2H, arom., J=7.0 Hz);6.69 (d, 2H, arom., J=7.0 Hz).

1.A.3)N′-(4-{4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamidehydrochloride

Intermediate 1.A.2 (0.5 g; 1.36 mmol) is dissolved in 2-propanol (15 ml)and 0.582 g of S-methyl-2-thiophene thiocarboximide hydroiodide (2.04mmol) (Ann. Chim., (1962), 7, 303-337) is added. After stirring at 25°C. for 15 hours, the reaction mixture is concentrated to dryness undervacuum. The residue is taken up in dichloromethane and a saturatedaqueous solution of NaHCO₃. After decantation, the organic phase iswashed successively with 50 ml of a saturated solution of NaHCO₃, withwater then with salt water. The organic solution is dried over magnesiumsulphate, followed by filtration and evaporation under reduced pressure.Then the free base is dissolved in 5 ml of ethanol and the solution iscooled down using an ice bath before the dropwise addition of 0.3 ml ofa 1N solution of HCl in anhydrous ethyl ether. After stirring for 15hours at 25° C., the crystals obtained are filtered and rinsed indiethyl ether in order to obtain after drying 0.320 g of a yellow solidproduct with a yield of 43%. Melting point: 203-203.7° C.

Process According to the Second Approach:

1.B.1) tert-butyl 4-(4-nitrophenyl)-1-piperazinecarboxylate

5.55 g (26.5 mmol) of 1-(4-nitrophenyl)piperazine is dissolved in amixture of 60 ml of dichloromethane and 8.2 ml of triethylamine. Themedium is cooled down using an ice bath before the addition of 6.4 g(29.2 mmol) of (Boc)₂O in several portions. The reaction mixture isstirred at 23° C. for 12 hours and poured into a water-ice mixture. Theorganic phase is decanted, washed successively with 20 ml of water and20 ml of salt water. After drying over sodium sulphate, filtration andconcentration under vacuum, then trituration with isopropyl ether, ayellow solid is obtained with a quantitative yield. Melting point:143.7-145.7° C.

1.B.2) tert-butyl 4-(4-aminophenyl)-1-piperazinecarboxylate

A solution of intermediate 1.B.1 (7.63 g; 25.0 mmol) in 40 ml of adichloromethane/ethanol mixture (30 ml/50 ml) as well as 1.0 g of 10%Pd/C is introduced into a stainless steel autoclave provided with amagnetic stirrer. The reaction mixture is stirred under hydrogenpressure (1.5 bars) for 12 hours at a temperature of 20° C. The Pd/C isthen eliminated by filtration and the filtrate is concentrated undervacuum. The evaporation residue is purified by trituration with ether, agrey powder is obtained (4.96 g; yield 71%). Melting point: 145° C.

1.B.3) tert-butyl4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-1-piperazinecarboxylate

Intermediate 1.B.2 (4.96 g; 17.9 mmol) is dissolved in 2-propanol (150ml) and 7.66 g of S-methyl-2-thiophene thiocarboxamide hydroiodide (26.8mmol) (Ann. Chim., (1962), 7, 303-337) is added. After stirring at 25°C. for 15 hours, the reaction mixture is concentrated to dryness undervacuum. The residue is taken up in dichloromethane and a saturatedaqueous solution of NaHCO₃. After decantation, the organic phase iswashed successively with 50 ml of a saturated solution of NaHCO₃, waterand salt water. The organic solution is dried over magnesium sulphate,followed by filtering and evaporating under reduced pressure. The solidobtained is filtered and rinsed in isopentane in order to obtain, afterdrying, 6.91 g of a yellow solid product (yield 78%). Melting point:164° C.

1.B.4) N′-[4-(1-piperazinyl)phenyl]-2-thiophenecarboximidamide

A stream of HCl gas is passed bubblewise through a solution at 0° C. ofintermediate 1.B.3 (5.40 g; 14.0 mmol) in ethyl acetate (200 ml). Themixture is left to return to ambient temperature overnight. A stream ofargon is passed through the reaction mixture, then the powder obtainedis filtered and washed with ethyl acetate in order to produce awhite-beige solid (5.0 g; yield 99%). Melting point: 180° C.

1.B.5)N′-(4-{4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamidehydrochloride

The experimental protocol used is similar to that described for compound1.A.1. The hydrochloride is produced in the same way as for intermediate1.A.3. The expected yellow solid is obtained.

Example 2N′-(4-{4-[2-(1,2-dithiolan-3-yl)acetyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide

The experimental protocol used is the same as that described forcompound 1, process A. Norlipoic acid, (Tetrahedron Letters (1997), 38(33), 5785-5788), replacing lipoic acid, in order to produce a yellowsolid (0 acid. 126 g).

MH⁺=433.2.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.97 (m, 1H, CH₂); 2.40 (m, 1H, CH₂); 2.75(m, 1H,CH₂); 2.87 (m, 1H,CH₂); 3.04 (m, 4H, CH₂-piperazine); 3.09 (m,1H,CH₂); 3.21 (m, 1H, CH₂); 3.59 (m, 4H, CH₂-piperazine); 3.97 (m, 1H,—S—CH—); 6.26 (broad s, 2H, NH₂); 6.76 (d, 2H, arom., J=8.6 Hz); 6.94(d, 2H, arom., J=8.6 Hz); 7.07 (m, 1H,CH-thiophene); 7.57 (m,1H,CH-thiophene); 7.70 (m, 1H,CH-thiophene).

Example 3N′-[3-({4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl}methyl)phenyl]-2-thiophenecarboximidamidehydrochloride

The experimental protocol used is the same as that described forcompound 1, process A. A white solid (0.220 g) is obtained. Meltingpoint: 240.0-240.5° C.

Example 4N′-[3-({4-[2-(1,2-dithiolan-3-yl)acetyl]-1-piperazinyl}methyl)phenyl]-2-thiophenecarboximidamide

The experimental protocol used is the same as that described forcompound 1, process A. Norlipoic acid, (Tetrahedron Letters (1997), 38(33), 5785-5788), replacing lipoic acid, in order to produce a yellowfoam (0.20 g).

MH⁺=447.2.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.96 (m, 1H, CH₂); 2.34-2.40 (m, 4H,CH₂-piperazine); 2.49 (m, 1H, CH₂); 2.71 (m, 1H,CH₂); 2.80 (m, 1H, CH₂);3.08 (m, 1H, CH₂); 3.28 (m, 1H, CH₂); 3.41 (m, 4H, CH₂-piperazine); 3.46(3, 2H, CH₂); 3.93 (m, 1H, —S—CH—); 6.54 (broad s, 2H, NH₂); 6.77 (d,1H, arom., J=7.60 Hz); 6.82 (s, 1H, arom); 6.95 (d, 1H, arom., J=7.60Hz); 7.10 (m, 1H,CH-thiophene); 7.26 (t, 1H, arom., J=7.60 Hz); 7.63 (m,1H, CH-thiophene); 7.74 (m, 1H, CH-thiophene).

Example 54-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide

0.206 g (1.0 mmol) of lipoic acid is solubilized under an argonatmosphere in dioxane (5 ml), acetonitrile (5 ml) and triethylamine (0.3ml). Diphenylphosphoryl azide (0.24 ml; 1.0 mmol) is added, then thereaction medium is taken to 80° C. for 2 hours. The reaction medium isthen cooled down using an ice bath, then intermediate 1.B.4 (0.395 g;1.0 mmol) is added. After having stirred the reaction mixture overnightat 25° C., the mixture is diluted with 100 ml of water and stirring iscontinued for another 30 minutes. The product is extracted using 3 times25 ml of ethyl acetate. The organic solution is dried over magnesiumsulphate, filtered and concentrated under vacuum. Purification on asilica column (eluent=10% of ethanol in dichloromethane) is then carriedout in order to produce a yellow solid. The yellow solid is furtherpurified by recrystallization from ethanol in order to produce 0.25 g ofproduct (yield 46.4%). Melting point: 201.1-201.8° C.

Example 6 4-(4-{[amino(2-thienyl)methylidene]amino}-2-methylphenyl)N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide 6.1. tert-butyl4-(2-methyl-4-nitrophenyl)-1-piperazinecarboxylate

4.65 g (3.10 mmol) of 2-fluoro-5-nitrotoluene, 6.71 g (3.60 mmol) oftert-butyl 1-piperazinecarboxylate and 10.4 g (7.50 mmol) of potassiumcarbonate are solubilized under an argon atmosphere, in dry DMF (50 ml),then the reaction medium is taken to 80° C. for 18 hours. The reactionmedium is then cooled down using an ice bath then poured into ice-coldwater. The product is extracted using 3 times 50 ml of ethyl acetate.The organic solution is dried over magnesium sulphate, followed byfiltration and concentration under vacuum. Purification is then carriedout by crystallization from diisopropyl ether and the solid obtained isfiltered and rinsed with isopentane in order to obtain, after drying,5.9 g of a yellow solid product (yield 62%). Melting point: 121.8-123.4°C.

6.2. tert-butyl 4-(4-amino-2-methylphenyl)-1-piperazinecarboxylate

The experimental protocol used is the same as that described forcompound 1.B.2. intermediate, 6.1 replacing intermediate 1.B.1 andethanol replacing the dichloromethane/ethanol mixture in order toproduce a beige foam which is sufficiently pure to be used in thefollowing stage (yield 98%)

MH⁺=292.20.

6.3. tert-butyl4-(4-{[amino(2-thienyl)methylidene]amino}-2-methylphenyl)-1-piperazinecarboxylate

The experimental protocol used is the same as that described forcompound 1.B.3., intermediate 6.2 replacing intermediate 1.B.2. Afterpurification by crystallization from ether, the solid obtained isfiltered and rinsed with diisopropyl ether, in order to obtain, afterdrying, a pale white-yellow solid product (yield 71%). Melting point:165° C.

6.4. N′-[3-methyl-4-(1-piperazinyl)phenyl]-2-thiophenecarboximidamidehydrochloride

The experimental protocol used is the same as that described forcompound 1.B.4., intermediate 6.3 replacing intermediate 1.B.3. Awhite-coloured solid-foam product is obtained (yield 95%).

MH⁺=301.20.

6. 5.4-(4-{[-amino(2-thienyl)methylidene]amino}-2-methylphenyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide

The experimental protocol used is the same as that described for thecompound of Example 5, intermediate 6.4 replacing intermediate 1.B.4. Ayellowish-white solid product is obtained (yield 3%). Melting point:193.3-194.6° C.

Example 74-(4-{[amino(2-thienyl)methylidene]amino}-3-methylphenyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide

The experimental protocol used is the same as that described for thecompound of Example 6, 5-fluoro-2-nitrotoluene replacing2-fluoro-5-nitrotoluene. A white solid product is obtained (yield 16%).Melting point: 169.4-170.9° C.

Example 84-(4-{[amino(2-thienyl)methylidene]amino}-2-methoxyphenyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide

The experimental protocol used is the same as that described for thecompound of Example 6, 2-chloro-5-nitroanisole replacing2-fluoro-5-nitrotoluene. A pale yellow solid product is obtained (yield25%). Melting point: 185.6-186.3° C.

Example 94-(4-{[amino(2-thienyl)methylidene]amino}-3-methoxyphenyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide

The experimental protocol used is the same as that described for thecompound of Example 6, 5-chloro-2-nitroanisole replacing2-fluoro-5-nitrotoluene. A pale yellow foam is obtained (yield 4%).

MH⁺=520.20.

Example 104-(4-{[amino(2-thienyl)methylidene]amino}-2-cyanophenyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide

The experimental protocol used is the same as that described for thecompound of Example 6, 2-fluoro-5-nitrobenzonitrile replacing2-fluoro-5-nitrotoluene. A yellow solid is obtained (yield 12%).

MH⁺=515.30.

Example 114-(3-{[amino(2-thienyl)methylidene]amino}benzyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide11.1. tert-butyl 4-(3-nitrobenzyl)-1-piperazinecarboxylate

5.00 g (2.30 mmol) of 3-nitrobromobenzyl and 4.53 g (2.40 mmol) oftert-butyl 1-piperazinecarboxylate are solubilized, under an argonatmosphere, in dichloromethane (100 ml), then triethylamine (8 ml) isadded dropwise. The reaction medium is stirred overnight at ambienttemperature before being poured into ice-cold water. The product isextracted using 3 times 150 ml of dichloromethane. The organic solutionis dried over magnesium sulphate, followed by filtration andconcentration under vacuum. Purification is then carried out on a silicacolumn (eluent=gradient ranging from pure heptane to pure ethyl acetate)in order to produce a yellow oil. After cold crystallization, 6.2 g of ayellow solid is obtained (yield 84%). Melting point: 85.5° C.

11.2. tert-butyl-4-(3-aminobenzyl)-1-piperazinecarboxylate

The experimental protocol used is the same as that described forcompound 1.A.2, intermediate 11.1 replacing intermediate 1.A.1. A yellowoil is obtained which, after cold crystallization, produces a yellowsolid (yield 98%). Melting point: 102.3° C.

11.3. Hydroiodide of tert-butyl4-(3-{[amino(2-thienyl)methylidene]amino}benzyl)-1-piperazinecarboxylate

The experimental protocol used is the same as that described forcompound 1.B.3, intermediate 11.2 replacing intermediate 1.B.2. A whitesolid is obtained. Melting point: 161.4° C.

11.4. N′-[3-(1-piperazinylmethyl)phenyl]-2-thiophenecarboximidamide

The experimental protocol used is the same as that described forcompound 1.B.4, intermediate 11.3 replacing intermediate 1.B.3. Ahygroscopic yellow solid is obtained (yield 72%).

MH⁺=301.10.

11.5.4-(3-{[amino(2-thienyl)methylidene]amino}benzyl)-N-[4-(1,2-dithiolan-3-yl)butyl]-1-piperazinecarboxamide

The experimental protocol used is the same as that described for thecompound of Example 5, intermediate 11.4 replacing intermediate 1.B.4. Apale yellow solid is obtained (yield 2%). Melting point: 152.0-153.4° C.

Example 12N′-(3-{4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl)phenyl)-2-thiophenecarboximidamide12.1. tert-butyl 4-(3-nitrophenyl)-1-piperazinecarboxylate

5.0 g (3.54 mmol) of 1-fluoro-3-nitrotoluene, 9.89 g (5.31 mmol) oftert-butyl 1-piperazinecarboxylate and 27.0 g (19.5 mmol) of potassiumcarbonate are solubilized under an argon atmosphere in DMSO (60 ml),then the reaction medium is taken to 100° C. for 72 hours. The reactionmedium is then cooled down using an ice bath then poured into ice-coldwater. The product is extracted using 3 times 50 ml of dichloromethane.The organic solution is dried over magnesium sulphate, followed byfiltration and concentration under vacuum. Purification on a silicacolumn is then carried out (eluent=heptane 70%/ethyl acetate 30%) inorder to produce a yellow solid. The yellow solid is further purified byrecrystallization from diisopropyl ether in order to produce 4.5 g ofthe expected product (yield 42.0%). Melting point: 82.0-92.0° C.

12.2. tert-butyl 4-(3-aminophenyl)-1-piperazinecarboxylate

The experimental protocol used is the same as that described forcompound 1.B.2, intermediate 13.1 replacing intermediate 1.B.1 and adichloromethane/THF mixture (50/50) replacing thedichloromethane/ethanol mixture. After purification by crystallizationfrom diisopropyl ether, a white solid is obtained (yield 25%). Meltingpoint: 218.0° C.

12.3. tert-butyl4-(3-{[amino(2-thienyl)methylidene]amino}phenyl)-1-piperazinecarboxylate

The experimental protocol used is the same as that described forcompound 1.B.3, intermediate 13.2 replacing intermediate 1.B.2. A paleyellow solid is obtained (yield 58%). Melting point: 150.0° C.

12.4.) N′-[3-(1-piperazinyl)phenyl]-2-thiophenecarboximidamidehydrochloride

The experimental protocol used is the same as that described forcompound 1.B.4, intermediate 13.2 replacing intermediate 1.B.3. Ayellow-beige coloured solid is obtained (yield 88%). Melting point:141.4° C.

12.5.N′-(3-(4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide

The experimental protocol used is similar to that described for compound1.A.1, intermediate 13.3 replacing the nitrophenylpiperazine. Theexpected product is obtained in the form of light yellow foam (yield63%).

MH+=475.20.

Example 13 tert-butyl5-{[amino(2-thienyl)methylidene]amino}-2-(4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl)benzylcarbamate13.1. 2-(4-benzyl-1-piperazinyl)-5-nitrobenzonitrile

The experimental protocol used is the same as that described forcompound 6.1, 2-fluoro-5-nitrobenzonitrile replacing2-fluoro-5-nitrotoluene and 1-benzylpiperazine replacing tert-butyl1-piperazinecarboxylate. A light ochre-coloured solid is obtained (yield89%). Melting point: 124.0° C.

13.2. [2-(4-benzyl-J-piperazinyl)-5-nitrophenyl]methanamine

3.90 g (1.21 mmol) of intermediate 14.1 is solubilized under an argonatmosphere in dry THF (40 ml) and a solution of diborane (1M in THF;24.2 ml; 2.42 mmol) is added dropwise before taking the resultingmixture to reflux for 1 hours. Methanol (5 ml) is added followed bystirring. HCl gas is then allowed to bubble through the reaction medium.After evaporation to dryness of the mixture, the residue is diluted withwater (50 ml), the solution is rendered alkaline with sodium bicarbonate(10%) and extracted with dichloromethane (3 times 100 ml). The organicsolution is then dried over magnesium sulphate, followed by filtrationand concentration under vacuum. Purification is then carried out on asilica column (eluent=dichloromethane containing 5% of ethanol) in orderto produce a brown oil (yield 42.0%).

MH+=327.20.

13.3. tert-butyl 2-(4-benzyl-1-piperazinyl)-5-nitrobenzylcarbamate

The experimental protocol used is the same as that described forcompound 1.B.1, intermediate 14.2 replacing the1-(4-nitrophenyl)piperazine and diisopropylethylamine replacing thetriethylamine. After purification on a silica column(eluent=dichloromethane containing 5% ethanol) a yellow oil (yield91.0%) is produced.

MH+=427.20.

13.4. tert-butyl 5-amino-2-(1-piperazinyl)benzylcarbamate

The experimental protocol used is the same as that described forcompound 1.B.2, intermediate 14.3 replacing intermediate 1.B.1 and adichloromethane THF mixture (50/50) replacing thedichloromethane/ethanol mixture. A white foam is obtained which issufficiently pure to be used in the following stage (yield 95%).

MH+=307.20.

13.5. tert-butyl5-{[amino(2-thienyl)methylidene]amino}-2-(1-piperazinyl)benzylcarbamate

The experimental protocol used is the same as that described forcompound 1.B.3, intermediate 14.4 replacing intermediate 1.B.2 whilsttwo equivalents of dried pyridine are added to the reaction medium. Ayellow foam is obtained after treatment, which is sufficiently pure tobe used in the following stage (yield 49%).

MH+=416.20.

13.6. tert-butyl5-{[amino(2-thienyl)methylidene]amino}-2-{4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl}benzylcarbamate

The experimental protocol used is similar to that described for compound1.A.1, intermediate 13.5 replacing the nitrophenylpiperazine. Theexpected product is obtained in the form of a white solid (yield 45%).Melting point: 162.4-164.0° C.

Example 14N′-(3-(aminomethyl)-4-{4-[5-(1,2-dithiolan-3-yl)pentanoyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide

The experimental protocol used is the same as that described forcompound 1.B.4, compound 13.6 replacing intermediate 1.B.3. A yellowsolid product is obtained (yield is 14%). Melting point: paste from 106°C.

Example 15 tert-butyl3-{[amino(2-thienyl)methylidene]amino}benzyl{1-[5-(1,2-dithiolan-3-yl)pentanoyl]-4-piperidinyl}carbamate15.1. N-(1-benzyl-4-piperidinyl)-N-(3-nitrobenzyl)amine

5.04 g (3.33 mmol) of 3-nitrobenzaldehyde and 7.48 ml (3.67 mmol) of4-amino-1-benzylpiperidine are added successively, under an inertatmosphere, to a flask containing 100 ml of anhydrous methanol. Thereaction mixture is stirred for 18 hours to produce the imine, then theaddition is carried out, of 1.26 g (3.33 mmol) of NaBH₄ in portions.Stirring is maintained for another 24 hours before the addition of 5 mlof ice-cold water. The reaction mixture is then extracted twice with 100ml of CH₂Cl₂. The organic phase is washed successively with 50 ml ofwater then 50 ml of salt water, dried over magnesium sulphate, filteredand concentrated under vacuum. The residue is purified on a silicacolumn (eluent: dichloromethane containing 5% of ethanol). A yellow oilis obtained with a yield of 85%.

MH+=316.20.

15.2. tert-butyl 1-benzyl-4-piperidinyl(3-nitrobenzyl)carbamate

The experimental protocol used is the same as that described forcompound 1.B.1, intermediate 15.1 replacing the1-(4-nitrophenyl)piperazine. After treatment, a yellow oil is obtainedwhich is sufficiently pure to be used in the following stage (yield99%).

MH+=426.30.

15.3. tert-butyl 3-aminobenzyl(4-piperidinyl)carbamate

The experimental protocol used is the same as that described forcompound 1.B.2, intermediate 15.2 replacing intermediate 1.B.1 and adichloromethane/THF mixture (50/50) replacing thedichloromethane/ethanol mixture. A white-grey foam is obtained which issufficiently pure to be used in the following stage (yield 63%).

MH+=306.30.

15.4. tert-butyl3-{[amino(2-thienyl)methylidene]amino}benzyl(4-piperidinyl)carbamate

The experimental protocol used is the same as that described forcompound 1.B.3, intermediate 16.3 replacing intermediate 1.B.2 whilsttwo equivalents of dry pyridine are added to the reaction medium. Afterpurification on a silica column (eluent: gradient ranging from puredichloromethane to dichloromethane containing 10% of ethanol containingtraces of ammonia), a yellowish-white foam is obtained, (yield 62%).

MH+=415.20.

15.5. tert-butyl3-{[-amino(2-thienyl)methylidene]amino}benzyl{1-[5-(1,2-dithiolan-3-yl)pentanoyl]-4-piperidinyl}carbamate

The experimental protocol used is similar to that described for compound1.A.1, intermediate 16.4 replacing the nitrophenylpiperazine. Theexpected product is obtained in the form of a yellowish foam (yield28%).

MH+=603.20.

Example 16N′-[3-[({1-5-(1,2-dithiolan-3-yl)pentanoyl]-4-piperidinyl}amino)methyl]phenyl)-2-thiophenecarboximidamide

The experimental protocol used is the same as that described forcompound 1.B.4, compound 15.5 replacing intermediate 1.B.3. A whitesolid is obtained (yield 33%).

MH+=503.31.

Example 17N-[2-(4-{[amino(2-thienyl)methylidene]amino}phenyl)ethyl]-4-{[5-(1,2-dithiolan-3-yl)pentanoyl]amino}benzamide17.1. 4-[(tert-butoxycarbonyl)amino]benzoic acid

The experimental protocol used is the same as that described forcompound 1.B.1, with 4-aminobenzoic acid replacing the1-(4-nitrophenyl)piperazine. A solid is obtained which is sufficientlypure to be used in the following stage (yield 23%).

MH+=238.

17.2. 3,5-dimethoxy-2-({[2-(4-nitrophenyl)ethyl]amino}methyl)phenol

9.0 g (49.4 mmol) of 4,6-dimethoxysalicaldehyde, 11.6 g (54.3 mmol) of4-nitrophenethylamine hydrochloride and 7.5 ml of triethylamine areadded successively into a flask containing 200 ml of anhydrous methanol,under an inert atmosphere. The reaction mixture is stirred vigorouslyfor 15 hours before the addition, in portions, of 2.1 g (55.5 mmol) ofNaBH₄. Stirring is maintained for an additional 10 hours before adding10 ml of water. After quarter of an hour, the reaction mixture isextracted with twice 100 ml of CH₂Cl₂. The organic phase is washedsuccessively with 50 ml of water and 50 ml of salt water, followed bydrying over sodium sulphate, filtering and concentration under vacuum.The residue is then purified on a silica column (eluent: CH₂Cl₂/EtOH:20/1). An orange oil is obtained with a yield of 58%.

17.3. tert-butyl2-hydroxy-4,6-dimethoxybenzyl[2-(4-nitrophenyl)ethyl]carbamate

30.0 mmol of intermediate 17.2 is dissolved in a mixture of 100 ml ofdichloromethane and 9.2 ml of triethylamine. The mixture is cooled downusing an ice bath before the addition in several portions of 7.2 g (33.0mmol) of (Boc)₂O. The reaction mixture is stirred at 23° C. for 12 hoursand poured into a water-ice mixture. The organic phase is decanted,followed by washing successively with 20 ml of water and 20 ml of saltwater. After drying over sodium sulphate, followed by filtration andconcentration under vacuum, a white solid is obtained after triturationwith isopropyl ether with a yield of 60%. Melting point: 133.5-134.4° C.

17.4. tert-butyl2-(4-aminophenyl)ethyl(2-hydroxy-4,6-dimethoxybenzyl)carbamate

A solution of intermediate 17.3 (20.2 mmol) in 66 ml of adichloromethane, ethyl acetate and THF mixture (1 ml/60 ml/5 ml) as wellas 1.0 g of 10% Pd/C is introduced into a stainless steel autoclaveprovided with a magnetic stirrer. The reaction mixture is stirred underhydrogen pressure (1.5 bars) for 12 hours at a temperature of 20° C. ThePd/C is then eliminated by filtration and the filtrate is concentratedunder vacuum. A light yellow oil is obtained with a yield of 90%.

17.5. tert-butyl2-(4-{[(amino(2-thienyl)methylidene]amino}phenyl)ethylcarbamate

Intermediate 17.4 (2.37 mmol) is dissolved in 2-propanol (15 ml) and1.014 g of S-methyl-2-thiophene thiocarboximide hydroiodide (3.56 mmol)(Ann. Chim. (1962), 7, 303-337) is added. After heating at 60° C. for 15hours, the reaction mixture is concentrated to dryness under vacuum. Theresidue is taken up in dichloromethane and a saturated aqueous solutionof NaHCO₃. After decantation, the organic phase is washed successivelywith 50 ml of a saturated solution of NaHCO₃, water and salt water. Theorganic solution is dried over magnesium sulphate, followed byfiltration and evaporation under reduced pressure. The free base is thendissolved in 30 ml of dichloromethane and the solution is cooled downusing an ice bath before the dropwise addition of 6.3 ml of a 1N HClsolution in anhydrous ethyl ether. After stirring for 15 hours at 25°C., the crystals obtained are filtered and rinsed in diethyl ether inorder to obtain, after drying, a yellow solid with a yield of 79%.Melting point: 144° C.

17.6. N′-[4-(2-aminoethyl)phenyl]-2-thiophenecarboximidamide

A stream of HCl gas is passed bubblewise at 0° C. through a solution ofintermediate 17.5 (16.4 mmol) in a mixture (200 ml) ofether/ethanol/acetone/dichloromethane (1/1/1/1). The reaction medium isleft to return to ambient temperature overnight. A stream of argon ispassed through the reaction mixture and the solvents are evaporated todryness. The evaporation residue is then poured into 100 ml of a coldsaturated solution of NaHCO₃ and extracted with 3 times 100 ml ofdichloromethane. The organic phase is dried over magnesium sulphate,followed by filtration and concentration under vacuum. Purification isthen carried out on a silica column (eluent=heptane with 50% ethylacetate then dichloromethane with 5. % ethanol) in order to produce awhite solid with a yield of 79%. Melting point: 169.2-170.5° C.

17.7.4-amino-N-[2-(4-{[amino(2-thienyl)methylidene]amino}phenyl)ethyl]-benzamide

The experimental protocol used is similar to that described for compound1.A.1, intermediate 17.1 replacing the (DL)-thioctic acid andintermediate 17.6 replacing the nitrophenylpiperazine. The expectedproduct is obtained in the form of a white foam with a yield of 35% (aswell as a secondary product, tert-butyl4-({[2-(4-{[amino(2-thienyl)methylidene]amino}phenyl)ethyl]amino}-carbonyl)phenylcarbamate,in the form of a white solid, with a yield of 14%).

MH+=365.20.

17.8.N-[2-(4-{[amino(2-thienyl)methylidene]amino}phenyl)ethyl]-4-{[5-(1,2-dithiolan-3-yl)pentanoyl]amino}benzamide

The experimental protocol used is similar to that described for compound1.A.1, intermediate 17.7 replacing the nitrophenylpiperazine. Theexpected product is obtained in the form of pale yellow crystals (yield17%).

MH+=553.10.

Pharmacological Study of the Products of the Invention:

Study of the Effects on Neuronal Constitutive NO Synthase of a Rat'sCerebellum

The inhibitory activity of the products of the invention is determinedby measuring their effects on the conversion by NO synthase of[³H]L-arginine to [³H]L-citrulline according to the modified process ofBredt and Snyder (Proc. Natl. Acad. Sci. USA, (1990) 87: 682-685). Thecerebellums of Sprague-Dawley rats (300 g—Charles River) are rapidlyremoved, dissected at 4° C. and homogenized in a volume of extractionbuffer (HEPES 50 mM, EDTA 1 mM, pH 7.4, pepstatin A 10 mg/ml, leupeptin10 mg/ml). The homogenates are then centrifuged at 21000 g for 15 min at4° C. Dosage is carried out in glass test tubes in which 100 μl ofincubation buffet containing 100 mM of HEPES (pH 7.4), 2 mM of EDTA, 2.5mM of CaCl₂, 2 mM of dithiotreitol, 2 mM of reduced NADPH and 10 μg/mlof calmodulin are distributed. 25 μl of a solution containing 100 nM of[³H]L-arginine (Specific activity 56.4 Ci/mmole, Amersham) and 40 μM ofnon-radioactive L-arginine are added. The reaction is initiated byadding 50 μl of homogenate, the final volume being 200 μl (the missing25 μl are either water or the tested product). After 15 minutes, thereaction is stopped with 2 ml of stopping buffer (20 mM of HEPES, pH5.5, 2 mM of EDTA). After placing the samples through a 1 ml column ofDOWEX resin, the radioactivity is quantified by a liquid scintillationspectrometer.

The compounds of Examples 1 to 6, 11, 12, 14 and 16 described above showan IC₅₀ lower than 4.5 μM.

Study of the Effects on the Oxidative Stress Induced by Glutamate onCells in Culture (HT-22):

The inhibitory activity of the products of the invention is determinedby measuring their ability to protect the cells of a mouse hippocampalcell line (HT-22) from oxidative stress caused by glutamate. Thebiosynthesis of glutathione, an essential element in cell detoxificationof free radicals, requires the active transport of cystine to inside thecell. The glutamate by opposing the penetration of cystine causes areduction in the level of gluthatione which leads to the death of thecell by oxidative stress (Demerle-Pallardy, C. et al., J. Neurochem.(2000), 74, 2079-2086; Davis, J. B. and Maher, P., Brain Res., (1994)652: 169-173; Murphy, T. H. et al., Neuron, (1989) 2: 1547-1558). Thecells are cultured at 37° C. in a DMEM medium with 10% of fetal calfserum added to it. The tests are carried out in 96-well platescontaining 5000 cells per well. The glutamate (5 mM) is added to themedium containing or not containing the products to be tested. The cellviability is tested after 24 hours by the MTT process (Hansen, M. B. etal., J. Immunol. Processes (1989) 119: 203-210). The ability of thecompounds to protect the cells from the toxic action of the glutamate isestimated in EC₅₀, calculated relative to the viability of cells whichhave not been subjected to the action of the glutamate considered as100% viability.

The compounds of Examples 1, 2, 4, 5 and 7 to 11 described above show anEC₅₀ lower or equal to 4 μM.

1-13. (canceled)
 14. A compound having a formula selected from the groupconsisting of

wherein n is an integer from 0 to 6: X′—Y′ is selected from the groupconsisting of —(CH₂)_(r)—, —(CH₂)_(r)—O—(CH₂)_(r)—,—(CH₂)_(r)—N(R₃)—(CH₂)_(r)—, —(CH₂)_(r)—CO(CH₂)_(r)—,—(CH₂)—CO—N(R₃)—(CH₂)_(r)—, —(CH₂)_(r)—N(R₄)—CO—(CH₂)_(r)— and—(CH₂)_(r)—N(R₃)—CO—N(R₄)—(CH₂)_(r)—, P is —(CH₂)_(g)—, g is an integerfrom 0 to 6, or P is

wherein R₆ is hydrogen, alkyl of 1 to 6 carbon atoms and —(CH₂)_(n)-Q′,Q′ is halogen, trifluoromethyl, hydroxy, amino, cyano,alkoxycarbonylamino, aralkoxycarbonylamino, alkoxy, alkylthio,alkylamino and dialkylamino, n is an integer from 0 to 6, or 4 isaromatic or non-aromatic heterocycle with 5 to 6 ring members with theheteroatoms being selected from the group consisting of —O—, —N(R₇)— and—S—, R₇ is hydrogen or alkyl of 1 to 6 carbon atoms; and A is

B is alkyl of 1 to 6 carbon atoms or carbocyclic or heterocyclic arylwith 5 or 6 ring members containing from 1 to 4 heteroatoms selectedfrom the group consisting of O, S, N, the aryl being unsubstituted orsubstituted by at least one member selected from the group consisting ofalkyl, alkenyl and alkoxy of up to 6 carbon atoms, or B is —NR₈R₉, inwhich R₈ and R₉ are individually selected from the group consisting ofhydrogen and alkyl of 1 to 6 carbon atoms, or one of R₈ and R₉ is nitrowhile the other is hydrogen or alkyl of 1 to 6 carbon atoms, or R₈ and Ntaken together form with the nitrogen atom a non-aromatic heterocyclewith five to six ring members, the elements of the chain being selectedfrom the group consisting of —CH₂—, —NH—, —O— and —S—, or B is SR₁₀, R₁₀is hydrogen or alkyl of 1 to 6 carbon atoms; the compounds (Xa) and(XIa) being such that their Ω heterocycle comprises nitrogen linkedrespectively to hydrogen or to a protective group of carbamate type Gp₂;X—Y as regards the compounds of formulae (II), (III) and (IV), Y is—O—(CH₂)_(r)— or —N(R₃)—(CH₂)_(r)— as regards the compounds of formulae(X) and (XI); Gp is a protective group of carbamate type, Gp₁ is aprotective group of benzyl type when Y is —O—(CH₂)_(r)— or a protectivegroup of carbamate type when Y is —N(R₃)—(CH₂)_(r)—; and r is an integerfrom 0 to 6.